1. Field of the Invention
This disclosure is related to the field of devices, methods, treatments and processes for atherosclerosis. Specifically, this disclosure relates to the use of low-dose pulsed RANKL can be used as a therapy for atherosclerosis.
2. Description of Related Art
The human skeletal system is a dynamic system—an individual's bone structure is constantly being remodeled. Bone consists of a protein matrix embedded in a mineral layer. Two cells play a key role in the ever-changing reconstruction of an individual's bone structure throughout his or her life: osteoclasts and osteoblasts. Osteoclasts are large multinucleated cells that are the principal, if not sole, bone resorbing cells in the body. Stated differently, and simply, osteoclasts are cells that remove bone tissue from the skeletal system through bone resorption; i.e., by removing and breaking up a bone's mineralized matrix. Osteoblasts, which are the cells responsible for bone formation, balance the function of osteoclasts. The activity of osteoblasts is regulated by several growth factors, including transforming growth factor beta and bone morphogenetic protein. Osteoblasts, in turn, regulate the production of osteoclasts by secreting macrophage colony stimulating factor (M-CSF) and displaying the receptor activator of NF-κB ligand (RANKL) on their cell surface to induce cells of the monocytic/macrophage lineage to develop into osteoclasts.
In healthy organisms, the two cells operate in homeostasis with the amount of bone resorption, and formation, being in harmony. Alteration of the carefully balanced roles of osteoclasts and osteoblasts in this dynamic system can result in the creation of certain problematic conditions. For example, increased activity of osteoblasts, but more commonly the decreased activity of osteoclasts, leads to osteoporosis, where the bones become overly dense leading to stress factures. In contrast, increased activity of osteoclasts or decreased activity of osteoblasts, leads to bone deconstruction which can manifest itself in osteoporosis and Paget's disease, which result in bones being fragile and brittle.
Recently, it has been discovered that the equilibrium of the skeletal system, skeletal homeostasis, does not operate in a vacuum but, rather, is dynamically influenced by the human immune system. For example, lymphocyte-derived cytokines, such as the receptor activator of NF-kB ligand (RANKL), interleukin (IL)-17 and type I and II interferons, are potent mediators of osteoclast function and osteoclastogenesis. Further, osteoclast activity and numbers are increased by cytokines produced by pro-inflammatory effector T-cells, augmentation of which leads to the bone erosion which occurs in inflammatory diseases such as rheumatoid arthritis and periodontitis. T-cell produced cytokines also play a critical role in bone cancers, post-menopausal osteoporosis, and in Paget's disease. This crosstalk between the immune and skeletal system has been termed osteoimmunology.
Currently, one way in which inflammation and bone-loss-based diseases, such as but not limited to osteoporosis, rheumatoid arthritis, periodontitis, Paget's disease and bone cancers, are treated is through multiple classes of anti-inflammatory agents including nonsteroidal anti-inflammatory agents/analgesics (NSAIDs), steroids and biologics that mediate the TNFα blockade. These forms of treatment address the effects of the disease; i.e., reducing inflammation, but do not directly counteract the underlying bone loss. Generally, these forms of treatment are effective in about 30-50% of patients. However, each of these classes of anti-inflammatory agents also have severe safety and adverse reaction issues, which tend to limit their use in specific populations.
Another treatment methodology for inflammatory and bone-loss-based diseases are drugs or biologics which directly treat osteoporosis and bone erosion. For example, bisphosphonates (also called diphosphonates) are a widely-prescribed class of drugs that prevent the loss of bone mass by inhibiting the digestion of bone though encouraging osteoclasts to undergo apoptosis, or cell death, thereby slowing bone loss. However, use of bisphosphonates comes with serious safety issues. First, osteonecrosis of the jaw is increased in patients taking bisphosphonates. Second, even though bisphosphonates slow bone loss, the risk of bone fracture in elderly patients is increased in patients on this class of drugs. This increase is most likely due to the fact that suppression of bone remodeling by bisphosphonates leads to an effete skeletal structure since bone remodeling (both the removal of old bone and new bone formation) is required to keep bone strength. As bisphosphonates are irreversible inhibitors, the removal of old bone in this carefully balanced system is suppressed, placing a patient at additional risk for a fracture.
Other biologics which directly treat osteoporosis and bone erosion include Denosumab, a fully human monoclonal antibody designed to block the effect of RANKL and possibly TNFα. However, higher incidences of infection have been reported in patients treated with Denosumab, possibly because of the off-target effect on TNFα. Another biologic is pulsed parathyroid hormone (PTH), a treatment which has been demonstrated to decrease bone fractures and increase bone density in postmenopausal osteoporosis. PTH targets osteoblasts to increase bone function and has shown great promise in the treatment of osteoporosis. However, the high cost of PTH (currently about $40,000 per year) has limited its use. Notably, neither PTH nor Denosumab have any noted effect of decreasing inflammation.
Osteoporosis is often associated with menopause (or any other loss of estrogen) in women and it has been established that osteoporosis is often associated with loss of estrogen. However, loss of estrogen also leads to other medical concerns. One of the more major of these is that loss of estrogen post-menopause also has been shown to lead to atherosclerosis (which is more commonly known as “coronary heart disease” or simply “heart disease”) and certain cancers.
Atherosclerosis is the hardening and narrowing of the arteries which slowly blocks them and restricts blood flow. If arteries become sufficiently narrow, they can chock off blood flow to vital organs (often the heart or brain) which can cause heart attacks and strokes, two of the leading causes of death and major hospitalization in the United States. Atherosclerosis begins with a thin layer of cells called the endothelium. The endothelium keeps the inside of arteries toned and smooth, which keeps blood flowing. When the endothelium is damaged (e.g. it develops legions) LDL cholesterol will enter the wall of the artery. Endothelium damage can be caused by a wide variety of factors, but many of the more recognized are smoking, high blood pressure, and high cholesterol.
When LDL cholesterol enters the wall of the artery, white blood cells will also enter the wall to digest the LDL. Over years, cholesterol and cells become plaque in the wall of the artery. These plaques result in the hardening and narrowing of the artery. They can also rupture allowing blood in the bloodstream to clot, which creates additional issues as the clot can result in a sudden loss of blood flow and be characteristic of a heart attack or stroke.
Atherosclerosis is incredibly common. It has been estimated that at least 50% of people over the age of 40 have it with as many as 85% of those over 50 having at least some formed plaques. While it is a disease generally associated with aging, at least one study has shown that 17% of teenagers still have some formed plaques as well. Interestingly, pre-menopausal women are at a reduced risk of atherosclerosis as naturally occurring estrogen appears to assist in both LDL cholesterol regulation and assists in resisting damage to the endothelium. However, post-menopause, the loss of estrogen results in women having an increased risk.
Atherosclerosis is, in many respects, untreatable. Once a plaque has formed it will be with the patient for the rest of their life. Thus, treatments often focus on reducing or eliminating the formation of plaques and many treatments focus on prevention. In particular, many treatments focus on traditional healthy living activities focusing on regular exercise and improved diet earlier in life.
Once Atherosclerosis reaches a certain stage, it is usually necessary to supplement preventative therapies with those that focus on minimizing effect. Drug therapies, therefore, often focus on redaction of exaggerating factors to slow plaque formation or build up. Typically, therapeutic avenues include ameliorating dyslipidemia (with statins, PCSK9 inhibitors, fibrates, or other inhibitors of dietary cholesterol absorption); ameliorating hypertension (with diuretics, angiotensin receptor blockers, Ca-channel blockers, or beta-blockers); or with anti-thrombotic agents (aspirin, clopidogrel, or warfarin). Once plaques become to large, bypass surgery or the introduction of stents is generally required.